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Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multi-centre studies are necessary to determine indications and establish common testing protocols.

Perioperative immediate hypersensitivity reactions are rare. Subsequent allergy investigation is complicated by multiple simultaneous drug exposures, the use of drugs with potent effects and the many differential diagnoses to hypersensitivity in the perioperative setting. The approach to the investigation of these complex reactions is not standardized, and it is becoming increasingly apparent that collaboration between experts in the field of allergy/immunology/dermatology and anaesthesiology is needed to provide the best possible care for these patients. The EAACI task force behind this position paper has therefore combined the expertise of allergists, immunologists and anaesthesiologists. The aims of this position paper were to provide recommendations for the investigation of immediate-type perioperative hypersensitivity reactions and to provide practical information that can assist clinicians in planning and carrying out investigations.

International audience

Background Neuromuscular blocking agents (NMBAs) are the main agents involved during perioperative immediate hypersensitivity. The etiological diagnosis (IgE-mediated allergy vs nonallergy) is linked to the clinical presentation together with tryptase and histamine levels and skin test results. The role of basophil activation test (BAT) needs to be better defined in this setting. Objectives To assess the role of BAT compared with the results of skin testing in 31 patients experiencing immediate NMBA hypersensitivity and compare skin test results and BAT performances in the identification of alternative NMBAs. Methods Histamine and tryptase levels were quantified. Anesthetic drugs, including NMBAs, were skin-tested. Basophil CD63 and CD203c expressions were measured in response to serial dilutions of the different NMBAs. Results Allergy and Nonallergy groups involved 19 and 12 patients, respectively. Circulating histamine and tryptase levels were significantly increased in allergic patients. In the Allergy group, while skin test results were positive in 100% (19 of 19) of the cases, BAT positivity to the culprit NMBA reached 78.9% (15 of 19) when combining CD63 and CD203c. NMBAs cross-reactivity was identified through skin testing and BAT in 36.8% (7 of 19) and 26.3% (5 of 19) of the cases, respectively. The concordance (culprit and cross-reactive NMBAs) between skin tests and BATs was between 73.6% (14 of 19) and 100% (19 of 19) for each NMBA. Negative skin-tested NMBAs were uneventfully used in 7 NMBA-allergic patients. In the Nonallergy group, skin test results were negative in 100% of the cases while BAT result was positive once (CD63 upregulation). Conclusion In our technical conditions, BAT does not replace skin testing in the assessment of NMBA allergy.

Resume Les mastocytoses sont caracterisees par l’accumulation anormale de mastocytes pathologiques dans divers tissus, principalement la peau, la moelle osseuse et le tube digestif. Les mastocytoses cutanees sont des affections benignes observees plutot chez l’enfant. Chez l’adulte, elles sont la plupart du temps systemiques et indolentes. Elles peuvent parfois etre agressives avec l’atteinte d’un ou plusieurs visceres ou tissus et/ou associees a une neoplasie hematologique. Les mastocytoses ne font pas partie des maladies allergiques. Elles sont en general liees a une mutation du recepteur a tyrosine kinase c-kit qui induit une accumulation clonale des mastocytes et leur activation constitutive. Quand elles sont presentes, les manifestations cliniques peroperatoires secondaires a la liberation de mediateurs par les mastocytes actives de facon non specifique sont en general de gravite mineure et limitees au territoire cutane et/ou au secteur vasculaire. Les signes cardiovasculaires ne sont pas correles au caractere systemique versus cutane de la maladie. Leur traitement est symptomatique. Certains facteurs favorisants d’ordre psychologique, pharmacologique (medicaments histaminoliberateurs), traumatique, mecanique et/ou thermique ont ete identifies. Leur eviction est recommandee dans la mesure du possible en fonction de chaque patient. L’interet d’une premedication par les antagonistes des recepteurs de type H 1 n’a pas ete prouve. Le dosage de la concentration de tryptase plasmatique peut etre realise lors du bilan preoperatoire. Seuls les patients ayant deja presente une reaction immediate peroperatoire doivent beneficier d’un bilan cutane afin de determiner le mecanisme physiopathologique de la reaction clinique, confirmer ou infirmer l’imputabilite d’un medicament de l’anesthesie et determiner une conduite a tenir pour les anesthesies ulterieures. Cette revue a pour but de rappeler les modalites de prise en charge peroperatoire des patients atteints de mastocytose.

This narrative review seeks to distinguish the clinical patterns of pre-existing allergic conditions from other confounding non-allergic clinical entities, and to identify the potential related risks and facilitate their perioperative management. Follow-up investigation should be performed after a perioperative immediate hypersensitivity to establish a diagnosis and provide advice for subsequent anaesthetics, the main risk factor for perioperative immunoglobulin E (IgE)-mediated anaphylaxis being a previous uninvestigated perioperative immediate hypersensitivity reaction. The concept of cross-reactivity between drugs used in the perioperative setting and food is often quoted, but usually not supported by evidence. There is no reason to avoid propofol in egg, soy, or peanut allergy. The allergenic determinants have been characterised for fish, shellfish, and povidone iodine, but remain unknown for iodinated contrast agents. Iodinated drugs may be used in seafood allergy. Evidence supporting the risk for protamine allergy in fish allergy and in neutral protamine Hagedorn insulin use is lacking. Conversely, cross-reactivity to gelatin-based colloid may occur in α-gal syndrome. Atopy and allergic asthma along with other non-allergic conditions, such as NSAID-exacerbated respiratory disease, chronic urticaria, mastocytosis, and hereditary or acquired angioedema, are not risk factors for IgE-mediated drug allergy, but there is a perioperative risk associated with the potential for exacerbation of the various conditions.

Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.

Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.

Background: Grading schemes for severity of suspected allergic reactions have been applied to the perioperative setting, but there is no scoring system that estimates the likelihood that the reaction is an immediate hypersensitivity reaction. Such a score would be useful in evaluating current and proposed tests for the diagnosis of suspected perioperative immediate hypersensitivity reactions and culprit agents. Methods: We conducted a Delphi consensus process involving a panel of 25 international multidisciplinary experts in suspected perioperative allergy. Items were ranked according to appropriateness (on a scale of 1-9) and consensus, which informed development of a clinical scoring system. The scoring system was assessed by comparing scores generated for a series of clinical scenarios against ratings of panel members. Supplementary scores for mast cell tryptase were generated. Results: Two rounds of the Delphi process achieved stopping criteria for all statements. From an initial 60 statements, 43 were rated appropriate (median score 7 or more) and met agreement criteria (disagreement index

"Iodine allergy" does not exist. The concept of "iodine allergy" should be abandoned since it may result in inappropriate measures such as drug, food or environmental eviction. Immediate or non-immediate allergic hypersensitivity to iodinated contrast media is not infrequent. The corresponding allergens have not been identified. Iodine is not involved. Immediate or non-immediate allergic hypersensitivity to povidone iodine is rare. The corresponding allergen is povidone in case of immediate hypersensitivity while nonoxynol might be involved during non-immediate hypersensitivity. Seafood allergens belong to a group of muscle proteins. Immediate drug hypersensitivity or food hypersensitivity is assessed by immediate-reading skin tests while non-immediate drug hypersensitivity is investigated by delayed-reading skin testing. Combined histamine and tryptase measurement is invaluable during the diagnostic approach of immediate hypersensitivity. Other biological tests are being evaluated. Allergic hypersensitivity to iodinated contrast agents does not contraindicate the use of other iodinated drugs.

International audience; Background:Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors.Methods:Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT.Findings:Among 245 skin-tested patients (ICM = 209; GBCM = 36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (p 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.

Background The role of the hypovolemic component secondary to the microcirculatory changes in the onset of inaugural anaphylactic hypotension remains debated. We investigated the microcirculatory permeability in a model of anaphylactic shock using a fluorescence confocal microscopy imaging system. Methods Ovalbumin-sensitized anesthetized Brown Norway rats were randomly allocated into two groups (n = 6/group): control and anaphylaxis, respectively induced by intravenous saline or ovalbumin at time 0 (T0). The mesentery was surgically exposed. Macromolecular fluorescein isothiocyanate-dextran was intravenously injected (T0-5min) allowing in vivo visualization of the mesenteric microvascular network by fluorescence microscopy. After a period of stabilization of the contrast agent concentration, a 5-s movie was recorded to obtain baseline signal intensity. Following T0, 5-s movies were recorded every 30 s for 30 min. Capillary leakage of fluorescein isothiocyanate-dextran was assessed in interstitium and compared between groups. Data are expressed as mean ± SD. Results Following anaphylactic shock onset, an early, progressive, and global signal intensity increase over time was detected in the interstitium. Mean index leakage differed between control and anaphylaxis (respectively 20 ± 11 vs. 170 ± 127%; P < 0.0001), starting at 2 min after shock onset and progressively increasing. Index leakage correlated with the drop in arterial blood pressure until T0 + 10 min (r = -0.75, P = 0.0001). Conclusions During anaphylaxis, interstitial capillary leakage occurs within minutes after shock onset. Compared with controls, the mesenteric microcirculation showed at least 8-fold-increased macromolecular capillary leakage. The inflammation-induced microcirculatory changes with subsequent intravascular fluid transfer might be involved in the onset of the inaugural hypotension during anaphylactic shock.

We report a case of transient symptomatic transferred IgE-mediated peanut allergy after elective blood-group compatible liver transplantation. We show that the allergy was transient and therefore passive, authorizing further uneventful peanut consumption. Skin tests with commercial peanut extract and native peanut were performed in the recipient. Circulating specific IgE against peanut and recombinant peanut allergens (rArah1, rArah2, rArah3) was measured in stored serum samples collected from the recipient between 6 months before and 8 months after liver transplantation. Specific IgE levels in the donor were measured at the time of multiorgan donation. In the recipient, diagnosis of IgE-mediated peanut anaphylaxis was based on the clinical history and detection of specific IgE against peanut and recombinant major peanut allergens (rArah1, rArah2 and rArah3). Skin tests were negative and specific IgE undetectable 6 months after the clinical reaction. Oral peanut challenge was negative excluding persistent peanut allergy. This case confirms that IgE-mediated peanut allergy can be transferred by liver transplantation and shows that it may be transient and therefore passively acquired.

During the preoperative evaluation, patients frequently indicate 'multiple drug allergies', most of which have not been validated. Potential allergic cross-reactivity between drugs and foods is frequently considered as a risk factor for perioperative hypersensitivity. The aim of this review is to facilitate the recognition of risk factors for perioperative anaphylaxis and help the management of patients with 'multiple drug allergies' during the perioperative period.Neuromuscular blocking agents (NMBAs) and antibiotics are the most common drugs triggering perioperative anaphylaxis. Quaternary ammonium ions have been suggested to be the allergenic determinant of NMBAs. Even though the 'pholcodine hypothesis' has been suggested to explain the occurrence of NMBA-induced allergy, this concept remains unclear. Although many practitioners believe that certain food allergies present an issue with the use of propofol, there is no role to contraindicate propofol in egg-allergic, soy-allergic or peanut-allergic patients. IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, but there is no cross-reactivity between them. The allergenic determinants have been characterized for fish, shellfish and povidone iodine and remain unknown for contrast agents.There are many false assumptions regarding drug allergies. The main goal of this article is to review the potential cross-reactivity among specific families of drugs and foods in order to facilitate the anesthetic management of patients with 'multiple drug allergies'.

We report a case of drug-induced immediate hypersensitivity occurring after atracurium injection in a patient with cutaneous mastocytosis.A 69-yr-old woman was scheduled for hysterectomy. She was premedicated with hydroxyzine, and anesthesia was induced with sufentanil, propofol, and atracurium. Within two to three minutes following the injection of atracurium, the patient experienced an episode of generalized erythema and arterial hypotension associated with tachycardia. No bronchospasm was observed. Her cardiovascular signs resolved spontaneously within five minutes, while her cutaneous signs disappeared within 30 min. Anesthesia and surgery remained uneventful. The patient's serum tryptase levels were measured at different time points following the clinical reaction. An in vitro flow cytometry-based basophil activation test was performed with atracurium, and in vivo skin tests to latex and all drugs which were administered just before the clinical reaction were also done. The serum tryptase showed increased concentrations that remained elevated for 24 hr, 48 hr, and even four weeks after the clinical reaction. Atracurium did not induce either CD63 or CD203c upregulation, and the skin tests were negative in response to the medications received (propofol, sufentanil, and atracurium) as well as to latex.Allergic hypersensitivity to atracurium was ruled out. Increased tryptase concentrations following the clinical reaction, persistent increased levels of basal serum tryptase, and negative skin tests suggested the onset of mast cell degranulation in a patient with mastocytosis. Immediate reaction occurring in patients with mastocytosis should be investigated in order to identify the mechanism of the reaction, either histamine release due to the disease itself or due to a concurrent drug/agent-induced IgE-mediated mechanism.

Apical ballooning syndrome, a reversible left ventricle dysfunction, has been reported following anaphylaxis and, during this clinical circumstance, is seemingly linked to the use of either low or high doses of epinephrine. We report a severe succinylcholine-induced IgE-mediated anaphylaxis in a 65-year-old woman, in whom the diagnosis of apical ballooning syndrome following anaphylaxis was established. As a thorough description of the clinical features and resuscitative measures could be obtained, we discuss the reasons for apical ballooning syndrome occurrence and highlight the fact that optimal care management of anaphylaxis should include a progressive titration of epinephrine.

Le diagnostic etiologique d'une reaction d'hypersensibilite immediate apres injection de produit de contraste (PC) est fonde sur un triptyque associant la description precise des symptomes observes, leur delai de survenue, le bilan biologique au decours de la reaction (histamine, tryptase) et les tests cutanes avec le PC administre. La confrontation de ces arguments permet d'identifier le mecanisme physiopathologique de la reaction et l'agent implique, s'il s'agit d'un mecanisme allergique. Le bilan cutane doit etre realise selon des criteres rigoureux, avec le PC incrimine, qui sera definitivement contre-indique si le test cutane est positif. Les autres PC seront aussi testes, afin de proposer pour les procedures ulterieures un PC donnant un test cutane negatif. L'expression « allergie a l'iode » doit etre bannie du vocabulaire medical, car l'atome d'iode lui-meme n'est pas l'allergene responsable de ces reactions. La premedication ne previent pas la survenue de reactions allergiques graves aux PC.

Resume Objectifs Presenter les differentes modalites de maitrise du risque allergique en anesthesie pediatrique. Type d’etude Analyse de la litterature. Methodes Recherche bibliographique, realisee a partir de la base de donnees Medline®, des publications parues en langue francaise et anglaise depuis 1982 a partir de mots-cles en format MeSH. Resultats L’incidence du risque allergique peranesthesique chez l’enfant est estimee a 1/7741 pour tous types d’anesthesies confondus. Ce risque est domine par l’allergie au latex avec une incidence de 1/10 159 anesthesies. Les facteurs de risque de sensibilisation au latex sont connus et la prevention primaire est efficace chez les patients a risque de sensibilisation au latex. A la difference de l’adulte, les curares sont rarement impliques chez l’enfant avec une frequence des reactions anaphylactiques de 1/81 275 pour tous types d’anesthesies confondus. Une classification clinique dite de Ring et Messmer permet de stratifier la gravite des reactions et de guider leur traitement. La symptomatologie clinique associe des signes cardiovasculaires, respiratoires et cutaneomuqueux selon un degre de gravite variable. Le traitement des reactions graves est fonde sur l’adrenaline associee a une expansion volemique. Le bilan allergologique fait partie integrante de la prise en charge du patient. Confronte a l’histoire clinique, il a pour but d’identifier le mecanisme physiopathologique de la reaction et le/la medicament/substance implique(e). Conclusion En anesthesie pediatrique, les reactions anaphylactiques dues aux curares sont rares alors qu’elles sont plus frequentes avec le latex. La maitrise de ce risque est, de fait, subordonnee en grande partie a l’eviction du latex.

Resume L’incidence et la morbimortalite des reactions allergiques de type immediat apres injection de produits de contraste iodes (PCI) demeurent inconnues. Le diagnostic etiologique d’une reaction d’hypersensibilite immediate apres injection de PCI est fonde sur un tryptique associant la description precise des signes cliniques inauguraux et leur delai de survenue, les resultats du bilan biologique preleve au decours de la reaction (histamine, tryptase) et les resultats des tests cutanes avec le PCI suspecte. La confrontation de ces arguments permet d’identifier le mecanisme physiopathologique de la reaction et l’allergene implique, s’il s’agit d’un mecanisme allergique. Le bilan cutane doit etre realise selon des criteres rigoureux. La recherche d’une reactivite cutanee avec les autres PCI commercialises permet de rechercher une sensibilisation croisee ; seuls les PCI non reactifs pourront etre proposes le cas echeant lors de procedures ulterieures. Le diagnostic d’allergie a un PCI impliquera l’eviction definitive de celui-ci mais non la contre-indication de l’ensemble des medicaments iodes. La sequence allergenique n’a pas ete identifiee mais ne correspond pas a l’atome d’iode lui-meme. L’asthme, la prise de β-bloquants ne constituent pas en tant que tels des facteurs de risque de survenue d’une reaction d’hypersensibilite allergique immediate aux PCI mais peuvent etre des facteurs aggravants. Les differents protocoles de premedication qui ont pu etre proposes ne previennent pas la survenue d’une reaction allergique/anaphylactique aux PCI. Seule l’eviction du PCI responsable permet d’eviter la recidive de la reaction.

Mastocytosis are characterized by an accumulation of abnormal mast cells in various tissues. Their incidence is estimated at 1/150,000 patients. Pure cutaneous mastocytosis which are mainly observed during childhood may resolve spontaneously during adolescence, whereas systemic mastocytosis involving one or more organs or tissues are more observed in adults. The initial event leading to mastocytosis is believed to be related to activating mutations in c-kit receptor, thus resulting in increased proliferation of mast cells precursors, migration in various tissues and degranulation leading to clinical signs. This nosologic entity does not belong to allergic diseases. Their perioperative management involves a multidisciplinary approach. The degranulation of mast cells with subsequent clinical symptoms can be triggered by psychological, chemical, traumatic, physical (rubbing, extreme temperatures...) agents. Avoiding these triggers should be realized whenever possible according to each patient. The premedication has not proven its efficiency. Tryptase measurement is part of the preoperative biological assessment. The clinical signs severity is related to the cardiovascular homeostasis disturbances (arterial hypotension, cardiovascular collapse, cardiac arrest). The cardiovascular symptoms do not correlate to the cutaneous versus systemic description of the disease. The drug of choice for the treatment of the severe cardiovascular signs is epinephrine associated to vascular loading. The aim of this literature review is to suggest the different modalities of perioperative care of patients with mastocytosis.

Background Epinephrine and more recently arginine vasopressin (AVP) alone or in combination have been proposed in patients with anaphylactic shock, but few experimental data exist. The authors investigated the effects of epinephrine only, AVP only, or epinephrine followed by AVP in a model of anaphylactic shock. Methods Ovalbumin-sensitized Brown Norway rats were anesthetized, intubated, and shock induced with ovalbumin. Rats (n = 6/group) were randomly allocated to receive 5 min after shock onset: (1) saline (no-treatment group); (2) two boluses of epinephrine followed by continuous infusion (epinephrine group); (3) AVP bolus followed by continuous infusion (AVP group); (4) epinephrine bolus followed by AVP continuous infusion (epinephrine + AVP group). Mean arterial pressure (MAP) and skeletal muscle oxygen pressure (PtiO2) were measured. Continuous infusion rates were titrated to reach MAP values of 60 mmHg. Survival was analyzed. Results Without treatment, MAP and PtiO2 decreased rapidly with 0% survival. In the epinephrine group, MAP and PtiO2 recovered after an initial decrease, with 84% survival. In the AVP group, MAP was partially restored and subsequently decreased; PtiO2 values decreased to values similar to those in the no-treatment group; survival was 0%. In the epinephrine + AVP group, MAP and PtiO2 values increased more slowly as compared with the epinephrine group; survival was 100%. Conclusions In this model of anaphylactic shock, early treatment with epinephrine followed by continuous epinephrine or vasopressin infusion resulted in an excellent survival rate, whereas vasopressin only resulted in a 100% death rate. These experimental results suggest that epinephrine must still be considered as the first-line drug to treat anaphylactic shock.

Care and therapy of patients experiencing an anaphylactic reaction should be known by the physicians working in the emergency medical unit or in pre-hospital care. The epidemiology of these reactions varies according to the countries. The main aetiologies are due to food, hymenoptera or drugs. The clinical scale proposed by Ring and Messmer aims to classify the reactions in 4 grades according to their severity and is useful to stratify therapy. According to the grade of the reaction, the drug of choice for the treatment of anaphylaxis is epinephrine associated to vascular expansion. Anaphylaxis during pregnancy is described. Patients who experienced an immediate hypersensitivity reaction should undergo an allergological investigation to prove the immune mechanism and to identify the culprit allergen. Reporting to the Drug Safety Monitoring Authorities when a drug is implicated should not be forgotten.

Perioperative anaphylaxis is a unique condition as a result of the additive cardiovascular effects of anesthetics on the cardiovascular disturbances of anaphylaxis. It occurs mainly in adulthood, primarily follows anesthetic induction, and for the most part, is an IgE-mediated pathomechanism. Neuromuscular blocking agents (NMBAs) and antibiotics are the main culprit drugs, while latex is now infrequently involved. The Ring and Messmer scale is a useful tool for demonstrating the clinical severity of perioperative immediate hypersensitivity and guiding its management. Grades III and IV are life-threatening and are referred to as anaphylaxis. Three different clinical patterns of grade III may be observed, where cardiovascular collapse is the cardinal sign. Grade IV presents as cardiac arrest. The initial diagnosis is presumptive, whereas the etiological assessment is linked to the clinical presentation, tryptase levels, and skin test results. Since anaphylaxis presents with significant hypovolemia and vasoplegia, aggressive fluid therapy and epinephrine are the cornerstones of management. Whenever possible, anesthetic discontinuation is also recommended. Scientific evidence in favor of preemptive therapeutic strategies to prevent anaphylaxis in the operative setting is lacking.

BACKGROUND: Artificial oxygen carriers such as perfluorocarbon (PFC) emulsions have reached Phase III clinical trials as alternatives to homologous blood, but their rheologic effects have not been characterized. In this study, the rheologic effects of PFC emulsion in the presence of clinically used volume expanders were investigated. STUDY DESIGN AND METHODS: The effects of a new PFC emulsion (small droplet size with narrow size distribution) at two PFC concentrations (4 and 8 g/dL) on plasma and whole-blood viscosity in the presence of human albumin solution (HAS), hydroxyethyl starch (HES), or modified fluid gelatin (MFG) were investigated. Three hematocrit (Hct) levels were investigated: 30, 20, and 13 percent. Plasma, PFC emulsions, and whole-blood viscosity, with a Couette viscometer, and RBC elongation, with an ektacytometer, were measured for shear rates of 0.2 to 128 per second. RESULTS: The two PFC concentrations increased plasma and whole-blood viscosities. Viscosity values similar to physiologic ones (Hct level, 40%) were observed at: 1) Hct level of 13 percent, with 4 or 8 g per dL MFG-PFC; 2) Hct level of 20 percent, with 4 g per dL MFG-PFC; and 3) Hct level of 30 percent, with 4 g per dL HES-PFC and 4 and 8 g per dL HAS-PFC. RBC deformability was unchanged. CONCLUSION: It is concluded that this new PFC emulsion increases plasma and blood viscosity and that among the three studied volume expanders, the interaction with MFG can result in viscosity values above the physiologic one even at low Hct values. The possible consequences of the increased viscosity at low Hct values are discussed.

Iodinated contrast media (CM) are widely used in radiological procedures, and carry a risk of adverse reactions with possible sequelae or death. Various and numerous reactions have been reported, most of which are transient ones and do not threaten the patients life. Immediate adverse reactions include adverse effects directly related to the osmotic load or to the CM chemotoxicity, and immediate hypersensitivity reactions. The exact incidence of the different types of reactions is difficult to establish because not all cases are reported and because a unique severity scale is lacking. All the underlying mechanisms have not been evidenced yet, as patients are rarely properly investigated. Allergic immediate hypersensitivity probably provokes the most severe reactions, whereas non-allergic hypersensitivity determines moderate reactions. Diagnostic tools are available and consist in tryptase and histamine measurements and in skin testing. Late reactions include skin or systemic reactions due to T-lymphocytes-mediated delayed hypersensitivity, nephropathy and dysthyroidism. Delayed allergic hypersentivity can be diagnosed by skin testing with delayed reading. Allergic hypersensitivity, immediate or delayed, means immune mechanisms and is a contraindication of further administration of the culprit CM.

Background Arginine vasopressin (AVP) and terlipressin were proposed as alternatives to catecholamines in shock states characterized by decreased plasma AVP concentrations. The endogenous plasma AVP profile in anaphylactic shock is unknown. In an ovalbumin-sensitized anesthetized anaphylactic shock rat model, the authors investigated (1) plasma AVP concentrations and (2) the dose versus mean arterial pressure response for exogenous AVP and terlipressin and compared them with those of epinephrine. Methods In a first series of rats (n = 12), endogenous plasma AVP concentrations were compared with a model of pharmacologically induced hypotension (nicardipine, n = 12). A second series was randomly assigned to three groups (AVP, n = 7; terlipressin, n = 7; epinephrine, n = 7) and dose (AVP: 8 doses, 0.03-100 U/kg; terlipressin: 7 doses, 0.03-30 microg/kg; epinephrine: 7 doses, 0.3-300 microg/kg)-response mean arterial pressure curves were plotted. Data are expressed as mean +/- SD. Results Endogenous plasma AVP concentrations were significantly lower in anaphylactic shock (57 +/- 26 pg/ml) than in the nicardipine group (91 +/- 43 pg/ml; P < 0.05). The ED50 was 10.6 microg/kg (95% confidence interval, 7.1-15.9) for epinephrine and 4.1 U/kg (95% confidence interval, 3.0-5.6) for AVP. Terlipressin did not change mean arterial pressure, regardless of the dose used. Conclusions In a rat model, anaphylactic shock is associated with inadequately low plasma AVP concentrations. For clinically relevant doses, AVP and epinephrine had comparable effects on mean arterial pressure and heart rate values, whereas, unexpectedly, terlipressin was ineffective. These results are consistent with reports in humans experiencing anaphylaxis where AVP injection restored arterial pressure.

Background The pathophysiology of anaphylactic shock during anesthesia is incompletely characterized. It is described as distributive by analogy with septic shock (anaerobic metabolism, high tissue oxygen pressure [Ptio2] values). The Ptio2 profile and its metabolic consequences during anaphylaxis are not known. Methods Ovalbumin-sensitized anaphylactic shock rats (n = 11) were compared to nicardipine-induced hypotension rats (n = 12) for systemic hemodynamics, Ptio2, sympathetic nervous system activation, skeletal muscle blood flow, and interstitial lactate and pyruvate concentrations using combined microdialysis and polarographic Clark-type oxygen probes. Results In both groups, the time course and the magnitude of arterial hypotension were similar. The ovalbumin group but not the nicardipine group displayed decreased skeletal muscle blood flow (from 45 +/- 6.2 ml x 100 g(-1) x min(-1) to 24.3 +/- 5 ml x 100 g(-1) x min(-1); P < 0.0001) and Ptio2 values (from 42 +/- 5 to 5 +/- 2; P < 0.0001). The ovalbumin group had more intense sympathetic nervous system activation with higher plasma epinephrine and interstitial norepinephrine concentrations. For the ovalbumin group, there was skeletal muscle anaerobic metabolism (lactate concentration increased from 0.446 +/- 0.105 to 1.741 +/- 0.459 mm; P < 0.05) and substrate depletion (pyruvate concentration decreased from 0.034 +/- 0.01 mm to 0.006 +/- 0.002 mm; P < 0.05) leading to increased interstitial lactate/pyruvate ratios (from 17 +/- 6 to 311 +/- 115; P < 0.05). Conclusions This profile suggests decreased skeletal muscle blood flow and oxygen delivery. Persistent energy consumption results in decreased Ptio2 and substrate depletion through anaerobic glycolysis leading to complete failure of cellular energy production. This could explain rapid organ dysfunction and resuscitation difficulties.

We report a grade III allergic hypersensitivity reaction occurring in a 72-year-old patient immediately after anaesthesia induction. Anaphylaxis to cisatracurium was diagnosed on clinical symptoms, biological tests and positivity of the cutaneous tests to this neuromuscular blocking agent. Five days after this allergological assessment, rocuronium, a muscle relaxant for which skin tests appeared negative was used during surgery without adverse effects. The authors underline the value of a detailed allergological assessment to identify the pathophysiologic mechanism, the culprit drug and to propose a safer alternate drug that might be used.

Methylene blue-treated fresh-frozen plasma (MB-FFP) is mainly used in Europe. The advantage of the methylene blue system is that units can be treated individually. The combined action of methylene blue and illumination is a photodynamic process preventing viral RNA and DNA replication. We report the first immediate allergic hypersensitivity reaction to methylene blue-treated plasma transfusion. The clinical course and subsequent assessment of the allergic reaction, including skin tests and basophil activation test, confirmed methylene blue-induced IgE-mediated anaphylaxis. All immediate reactions after MB-FFP transfusion should be investigated to document the underlying mechanism.

"Iodine allergy" does not exist. The concept of "iodine allergy" should be abandoned since it may result in inappropriate measures such as drug, food or environmental eviction. Immediate or non-immediate allergic hypersensitivity to iodinated contrast media is not infrequent. The corresponding allergens have not been identified. Iodine is not involved. Immediate or non-immediate allergic hypersensitivity to povidone iodine is rare. The corresponding allergen is povidone in case of immediate hypersensitivity while nonoxynol might be involved during non-immediate hypersensitivity. Seafood allergens belong to a group of muscle proteins. Immediate drug hypersensitivity or food hypersensitivity is assessed by immediate-reading skin tests while non-immediate drug hypersensitivity is investigated by delayed-reading skin testing. Combined histamine and tryptase measurement is invaluable during the diagnostic approach of immediate hypersensitivity. Other biological tests are being evaluated. Allergic hypersensitivity to iodinated contrast agents does not contraindicate the use of other iodinated drugs.

We report a case of immediate allergic hypersensitivity following intra-articular injection of ioxaglate and cortivazol. Allergic hypersensitivity to ioxaglate was confirmed through skin test positivity. No cross-reactivity with the other skin-tested iodinated contrast agents was observed. Allergic hypersensitivity to cortivazol was ruled out. Flow cytometry-based basophil activation test corroborated with skin tests results. The detection of sensitized basophils by flow cytometry associated with the clinical history and skin tests can be useful to confirm the diagnosis of immediate allergic hypersensitivity and provide advice for further procedures. Finally, this case confirms the need for systematic allergological investigation in cases of immediate hypersensitivity, whatever the mode of drug administration, in order to avoid the culprit allergen in the future.

The prevalence of anaphylaxis occurring during pregnancy is approximately 3 cases per 100,000 deliveries. The management of anaphylaxis occurring during the third trimester of pregnancy may be challenging because of the additive effects of aortocaval compression and cardiovascular disturbances of anaphylaxis. In this review, we identify the clinical signs of anaphylaxis occurring during labor and cesarean delivery, discuss the more common allergens that cause anaphylaxis during this clinical setting, and develop a rational approach to the identification of the offending allergen. We also suggest strategies for the management of anaphylaxis occurring during the third trimester of pregnancy, including the prompt administration of epinephrine and emergency cesarean delivery in cases of severe reactions. Evidence is limited to case reports and extrapolation from nonfatal and fatal cases, interpretation of pathophysiology, and consensus opinion.

New Zealand male rabbits were anaesthetized with thiopental, tracheotomized, curarized by vecuronium bromide and mechanically ventilated. Six rabbits received L-NAME 10 mg kg -1 i.v., six rabbits L-NAME 15 mg kg -1 iv, and six rabbits received saline i.v. (controls), 5 min before a histamine aerosol (2% solution during 5 min). Six others rabbits received an injection of L-NAME 15 mg kg -1 iv, 5 min before the histamine aerosol, followed by an infusion of L-arginine over a 60- min period. Total respiratory resistance (Rrs) and elastance (Ers) were derived by least square analysis of the relationship between tracheal pressure and flow, and computed every minute before and over a 1-h period after the histamine aerosol. Oxygen free radicals (OFR) were measured with a luminometer, in microsomes from lung homogenates at the end of the experiment. Compared with the histamine response of the control group, the Rrs response in the L-NAME 10 group was slightly less, while Ers changes were the same in the two groups. In contrast, L-NAME 15 was responsible for an increased Rrs response, the difference being significant (P < 0.05) only between 15 and 40 min after the aerosol (+114% vs. + 85% in controls at the 20th min). The increase in Ers with L-NAME 15 was stronger and significantly larger (+71% vs. +42% in controls at the 20th min after the histamine aerosol, P < 0.001). The relatively greater effect of L-NAME on Ers than on Rrs suggests that NO predominantly modulates the response to histamine of the peripheral lung rather than that of the large airways. Furthermore, the effect of L-NAME on Rrs was completely abolished by L-arginine, while its effect on Ers was only partially reversed. This suggests that the changes in Ers are partly related to a hardly reversible phenomenon. Possibly, the mechanical changes are linked with the rise of OFR in the lung parenchyma, which were significantly higher in the L-NAME 15 group compared to the control group (P < 0.05).

This article has been selected for the ANESTHESIOLOGY CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue.

IgE-mediated anaphylaxis remains one of the rare but significant events specifically related to contrast agents or drugs used during the perioperative period that can lead to morbidity and mortality. Its clinical diagnosis, initially presumptive, is not always obvious. However, anesthesiologists and radiologists must know the different clinical symptoms heralding anaphylaxis in order to provide the appropriate care management according to the severity of the clinical reaction. Clinical signs are described by the Ring and Messmer four-step grading scale, which also helps to guide care according to the severity of the reaction. Grade I and II reactions are usually not life-threatening. Conversely, Grade III and IV reactions are likely to be life threatening and require immediate resuscitative measures including epinephrine and fluid therapy. Early administration of epinephrine remains the cornerstone of anaphylaxis treatment; the appropriate dose should be administered according to the clinical picture. Biochemical tests, either in vivo or in vitro, including at least tryptase level are measured following the clinical reaction, and may help to prove its pathomechanism. Skin tests remain the gold standard for the detection of IgE-mediated reactions and should be performed according to strict rules. Skin tests remain the cornerstone of the allergological assessment in order to identify the culprit agent, prove the pathomechanism of the reaction and provide advice for further procedures. Accordingly, this review also focuses on the clinical pathway used to reintroduce a contrast agent or a neuromuscular blocking agent in patients having presented a documented anaphylactic response to one of these drugs.

To the Editor: Manivannan et al1 published a useful case of apical ballooning syndrome (ABS) after intravenous administration of epinephrine for anaphylaxis. The authors rightly underscored that high doses of intravenous epinephrine may induce ABS. However, specific concerns are warranted regarding some key points. Specifically, ABS occurring after anaphylaxis seems to be related to inappropriate use of epinephrine, including intravenous and intramuscular injections as well as high or low doses. Five clinical cases have been reported for ABS after epinephrine administration for anaphylaxis (Table).2-6 Han and Yeon2 reported the first case, in which 0.2 mg of epinephrine was intravenously injected during moderate anaphylaxis. The authors considered that the midventricular hypokinesis was related to a cardiac manifestation of anaphylaxis. Cabaton et al3 and Suk et al5 reported ABS after perioperative anaphylaxis. Cabaton et al3 showed that epinephrine, even when injected at low intravenous doses, may have been involved in the occurrence of ABS. In this case, the 2 last boluses of epinephrine (0.1 mg × 2) were injected after generalized cutaneous signs appeared (indicating hemodynamic restoration) and were immediately followed by ventricular fibrillation. Suk et al5 reported ABS after a high dose (1 mg) of intravenous epinephrine associated with a norepinephrine infusion. The authors suggested that excessive catecholamine surges in response to anaphylaxis and/or to the administration of exogenous catecholamines may have played a role in the ABS occurrence. In the case published by Manivannan et al,1 2 intravenous doses of 0.5 mg of epinephrine were injected in the absence of cardiovascular disturbances. Hypotension occurring after the first bolus of epinephrine was related to an adverse cardiac response to epinephrine. TABLE. Clinical Cases of ABS After Epinephrine Injection During Anaphylaxisa,b Zubrinich et al4 and Litvinov et al6 reported ABS after intramuscular injection of epinephrine. The former concluded that, given the mild clinical presentation, epinephrine (0.3 mg) should not have been used.4 The latter confirmed a direct causal role for suprapharmacologic doses of exogenous epinephrine (5 mg) in the pathophysiology of ABS.6 The dangers of epinephrine administration outside the context of severe anaphylaxis have been highlighted by the reports of serious outcomes. Recently, pharmacologic and suprapharmacologic doses of epinephrine have been reported to induce one of the 3 ABS variants.6 The catechol O-methyltransferase genotype and intense psychological stress may also influence predisposition to ABS.1,6 Finally, all the reported patients1-6 fulfilled Mayo Clinic criteria for ABS.1 Thus, as suggested during perioperative anaphylaxis, treatment may be initiated according to a 4-step clinical grading scale.7 Whereas grade 1 involves cutaneous-mucous signs in which epinephrine should never be injected, grade 2 corresponds to mild cutaneous-mucous features that may be associated with cardiovascular and/or respiratory signs for which titrated intravenous boluses (0.01-0.02 mg) of epinephrine may sometimes be necessary. The hallmark of grade 3 is cardiovascular collapse that may be associated with cutaneous-mucous signs and/or bronchospasm; titrated intravenous bolus administration of epinephrine (0.1-0.2 mg) is required and should be renewed if necessary. Finally, grade 4 is cardiac arrest that requires high doses of epinephrine, as warranted during cardiopulmonary resuscitation. The important issue is not the route of epinephrine administration, but its appropriate use during anaphylaxis. Consequently, these cases emphasize the need for careful patient selection and titration of epinephrine when the clinical situation dictates its use.

1Assistance Publique Hopitaux de Paris, Hopital Necker-Enfants Malades, Service d’Anesthesie-Reanimation & SAMU de Paris, Universite Paris-Descartes, INSERM U970, Paris, France 2Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Service d’Anesthesie-Reanimation Chirurgicale, Paris, France 3Assistance Publique Hopitaux de Paris, Hopital Bichat-Claude Bernard, Unite d’Immunologie Auto-immunite & Hypersensibilites, Paris, France 4Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Service de Pharmacie, Paris, France 5Assistance Publique Hopitaux de Paris, Hopital Necker-Enfants Malades, Service de Pharmacie, Paris, France 6Assistance Publique Hopitaux de Paris, Hopital Bichat-Claude Bernard, Unite d’Immunologie Auto-immunite & Hypersensibilites, Paris & Universite Paris-Sud11, INSERM UMRS-996, Châtenay-Malabry, France 7Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Service de Pharmacie, Paris, France 8Pole d’Anesthesie-Reanimation Chirurgicale, CHU Hopital Central, Nancy, France

Resume Le but de ce travail a ete de comparer les effets rheologiques sanguins d'une perfusion de 500 ml de substitut plasmatique administree lors de l'induction anesthesique chez 60 patients ASA1, repartis au hasard apres tirage au sort, en 6 groupes de 10 patients. Chaque groupe recevait soit de l'albumine a 4 %, soit du dextran 40 a 3,5 %, soit du dextran 60 a 6 %, soit de l'hydroxyethylamidon 200 a 6 %, soit de la gelatine fluide modifiee, soit du Ringer lactate. Les prelevements sanguins ont ete effectues avant la perfusion, immediatement apres la fin de la perfusion, puis 3 et 24 heures apres. Les parametres biochimiques mesures ont ete la pression osmotique par cryoscopie, la pression oncotique par filtration, les protides totaux (methode du biuret) et le fibrinogene (methode de Von Clauss). Les parametres rheologiques etudies ont ete la viscosite plasmatique (viscosimetre capillaire), la viscosite sanguine a deux vitesses de cisaillement : 0,5 et 128 s−1 (viscosimetre de type Couette) et l'agregation des hematies avec etude des temps primaire et final d'agregation et des seuils de dissociation partielle et totale (erythroagregametre). Les mesures ont ete faites apres ajustement de l'hematocrite a 40 %. L'etude statistique a consiste en une analyse de variance intergroupe puis intragroupe, a l'aide du test non parametrique de Kruskal-Wallis. Le seuil de signification retenu a ete p

Clinical guidelines for anaphylaxis recommend epinephrine as first-line therapy but do not distinguish between early and late stages of anaphylaxis. The delay between the onset of anaphylaxis and initiation of treatment may influence the choice of the optimal vasoconstrictor (epinephrine versus arginine vasopressin [AVP]). Anesthetized rats were allocated into control and three anaphylaxis groups (n = 6 per group). The aortas were removed at 5 min (control) and at 5, 15, or 30 min during anaphylaxis and were contracted in organ baths by increasing concentrations of epinephrine or AVP. After washout of the initial agonist, each ring was contracted with the alternative drug. Separately, aortic rings removed during early versus late anaphylaxis were contracted by AVP +/- pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (10 M), a NOS inhibitor. Aortic rings removed during late versus early anaphylaxis were less responsive to epinephrine (EC50 at 5 min, 8.4 nM [4.9 - 11.8]; EC50 at 30 min, 18.2 nM [11.9 - 24.4]; P = 0.04) and AVP (EC50 at 5 min, 8.1 nM [4.9 - 11.3]; EC50 at 30 min, 19.7 nM [10.9 - 28.6]; P = 0.02). Pre-exposure to AVP enhanced the subsequent contractile effect of epinephrine in aortic rings removed during late anaphylaxis (maximal contractile effect, 1.02 g [0.76 - 1.28]) versus early anaphylaxis (maximal contractile effect, 0.44 g [0.28 - 0.59]; P = 0.005). In contrast to early anaphylaxis, pretreatment with L-NAME decreased responsiveness to AVP during late anaphylaxis (EC50, 2.47 nM [1.79 - 3.16], 1.55 nM [1.11 - 1.98] for +/- L-NAME, respectively; P = 0.03). During anaphylaxis, the vasoconstrictive effects of AVP or epinephrine were time dependent. Arginine vasopressin might have beneficial effects during late anaphylaxis via mechanisms involving NO.